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Regulation of proteolytic processing of the amyloid β-protein precursor of Alzheimer’s disease in transfected cell lines and in brain slices

  • R. M. Nitsch
  • B. E. Slack
  • S. A. Farber
  • J. G. Schulz
  • M. Deng
  • C. Kim
  • P. R. Borghesani
  • W. Korver
  • R. J. Wurtman
  • J. H. Growdon
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 44)

Summary

βA4 is the principal component of Alzheimer’s disease brain amyloid. It is derived from proteolytic processing of amyloid β-protein precursors (APP), a family of transmembrane glycoproteins. Secretion of APPs, a secreted proteolytic derivative that is cleaved within the βA4 domain of APP, is increased many-fold by the activation of cell-surface receptors, like the muscarinic m1 and m3 receptor subtypes, which are coupled to protein kinase C. Concomitantly, their activation decreases the formation of both secreted soluble βA4 and of endosomal-lysosomal C-terminal APP derivatives. These data suggest that muscarinic m1 and m3 receptors accelerate non-amyloidogenic APP processing and depress the formation of potentially amyloidogenic derivatives. Other receptors that stimulate APPs secretion include those for bradykinin, vasopressin, and interleukin-1 receptors. A similar control mechanism is present in rat brain tissue slices, in which the release of both APPs and endogenous neurotransmitters is increased by electrical depolarization. This increase is tetrodotoxin-sensitive and frequency-dependent, suggesting that APPs release may normally depend on neuronal activity. Taken together, our findings suggest that specific receptor agonists might be effective in reducing the formation of potentially amyloidogenic APP derivatives in vivo.

Keywords

Chelerythrine Chloride Specific Receptor Agonist Electrical Depolarization Swedish Double Mutation Amyloidogenic Derivative 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • R. M. Nitsch
    • 2
  • B. E. Slack
    • 1
  • S. A. Farber
    • 1
  • J. G. Schulz
    • 1
  • M. Deng
    • 1
  • C. Kim
    • 1
  • P. R. Borghesani
    • 1
  • W. Korver
    • 1
  • R. J. Wurtman
    • 1
  • J. H. Growdon
    • 2
  1. 1.Department of Brain and Cognitive Sciences, E25-604Massachussetts Institute of TechnologyCambridgeUSA
  2. 2.Department of NeurologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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